This invention relates to a process for preparing 3-amino-1,2,4-benzotriazine 1,4-dioxide known under the nonproprietary name tirapazamine.
Tirapazamine is disclosed in U.S. Pat. No. 5,175,287 as a radiosensitizer and selective cytotoxic agent for hypoxic tumor cells, and U.S. Pat. No. 5,484,612 discloses that tirapazamine enhances the cytotoxicity of chemotherapy agents.
The preparation of tirapazamine is disclosed in Angew. Chem. 84, 1061 (1972) and in U.S. Pat. No. 3,868,371. The process involves reaction of benzofuroxan with disodium cyanamide in aqueous methanol followed by acidification with acetic acid to give 3-amino-1,2,4-benzotriazine 1,4-dioxide. U.S. Pat. No. 5,672,702 discloses an improved process for preparing tirapazamine of high purity which involves reaction of benzofuroxan with disodium cyanamide in aqueous dimethyl sulfoxide followed by acidification with methanesulfonic acid and crystallization from sodium acetate buffer.
The above processes are exothermic, and while controllable on a small scale, pose the risk of a dangerous runaway exothermic reaction when carried out on an industrial scale. This risk is, of course, magnified by the fact that tirapazamine is a cytotoxic agent. Reducing the scale on which the reaction is carried out in order to avoid this disadvantage, of course, defeats the purpose of an industrial production process. Moreover, even if the exothermic reaction could be controlled, the above processes are carried out in strongly basic aqueous medium, conditions under which tirapazamine is unstable. Therefore, both the yield and the purity of the resulting product are diminished. Thus, there is a need for a safe industrial process for producing tirapazamine and one in which tirapazamine is stable.